|
|
|
|
Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders
|
|
|
|
|
|
|
|
نویسنده
|
leblond c.s. ,heinrich j. ,delorme r. ,proepper c. ,betancur c. ,huguet g. ,konyukh m. ,chaste p. ,ey e. ,rastam m. ,anckarsäter h. ,nygren g. ,gillberg i.c. ,melke j. ,toro r. ,regnault b. ,fauchereau f. ,mercati o. ,lemière n. ,skuse d. ,poot m. ,holt r. ,monaco a.p. ,järvelä i. ,kantojärvi k. ,vanhala r. ,curran s. ,collier d.a. ,bolton p. ,chiocchetti a. ,klauck s.m. ,poustka f. ,freitag c.m. ,waltes r. ,kopp m. ,duketis e. ,bacchelli e. ,minopoli f. ,ruta l. ,battaglia a. ,mazzone l. ,maestrini e. ,sequeira a.f. ,oliveira b. ,vicente a. ,oliveira g. ,pinto d. ,scherer s.w. ,zelenika d. ,delepine m. ,lathrop m. ,bonneau d. ,guinchat v. ,devillard f. ,assouline b. ,mouren m.-c. ,leboyer m. ,gillberg c. ,boeckers t.m. ,bourgeron t.
|
|
منبع
|
plos genetics - 2012 - دوره : 8 - شماره : 2
|
|
چکیده
|
Autism spectrum disorders (asd) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. while many rare variants in synaptic proteins have been identified in patients with asd,little is known about their effects at the synapse and their interactions with other genetic variations. here,following the discovery of two de novo shank2 deletions by the autism genome project,we identified a novel 421 kb de novo shank2 deletion in a patient with autism. we then sequenced shank2 in 455 patients with asd and 431 controls and integrated these results with those reported by berkel et al. 2010 (n = 396 patients and n = 659 controls). we observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (p = 0.004,or = 2.37,95% ci = 1.23-4.70). in neuronal cell cultures,the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (p = 0.0013). interestingly,the three patients with de novo shank2 deletions also carried inherited cnvs at 15q11-q13 previously associated with neuropsychiatric disorders. in two cases,the nicotinic receptor chrna7 was duplicated and in one case the synaptic translation repressor cyfip1 was deleted. these results strengthen the role of synaptic gene dysfunction in asd but also highlight the presence of putative modifier genes,which is in keeping with the multiple hit model for asd. a better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of asd. © 2012 leblond et al.
|
|
|
|
|
آدرس
|
human genetics and cognitive functions,institut pasteur,paris,france,cnrs ura 2182 genes,synapses and cognition,institut pasteur,paris,france,university denis diderot paris 7,paris, France, institute of anatomy and cell biology,ulm university,ulm, Germany, human genetics and cognitive functions,institut pasteur,paris,france,cnrs ura 2182 genes,synapses and cognition,institut pasteur,paris,france,assistance publique-hôpitaux de paris,robert debré hospital,department of child and adolescent psychiatry,paris, France, institute of anatomy and cell biology,ulm university,ulm, Germany, inserm,u952,paris,france,cnrs,umr 7224,paris,france,upmc univ paris 06,paris, France, human genetics and cognitive functions,institut pasteur,paris,france,cnrs ura 2182 genes,synapses and cognition,institut pasteur,paris,france,university denis diderot paris 7,paris, France, human genetics and cognitive functions,institut pasteur,paris,france,cnrs ura 2182 genes,synapses and cognition,institut pasteur,paris,france,university denis diderot paris 7,paris, France, human genetics and cognitive functions,institut pasteur,paris,france,cnrs ura 2182 genes,synapses and cognition,institut pasteur,paris,france,university denis diderot paris 7,paris, France, human genetics and cognitive functions,institut pasteur,paris,france,cnrs ura 2182 genes,synapses and cognition,institut pasteur,paris,france,university denis diderot paris 7,paris, France, department of clinical sciences in lund,lund university,lund, Sweden, institute of clinical sciences,lund university,malmö, Sweden, gillberg neuropsychiatry centre,university of gothenburg,göteborg, Sweden, gillberg neuropsychiatry centre,university of gothenburg,göteborg, Sweden, institute of neuroscience and physiology,department of pharmacology,gothenburg university,göteborg, Sweden, human genetics and cognitive functions,institut pasteur,paris,france,cnrs ura 2182 genes,synapses and cognition,institut pasteur,paris,france,university denis diderot paris 7,paris, France, eukaryote genotyping platform,genopole,institut pasteur,paris, France, human genetics and cognitive functions,institut pasteur,paris,france,cnrs ura 2182 genes,synapses and cognition,institut pasteur,paris,france,university denis diderot paris 7,paris, France, human genetics and cognitive functions,institut pasteur,paris,france,cnrs ura 2182 genes,synapses and cognition,institut pasteur,paris,france,university denis diderot paris 7,paris, France, human genetics and cognitive functions,institut pasteur,paris,france,cnrs ura 2182 genes,synapses and cognition,institut pasteur,paris,france,university denis diderot paris 7,paris, France, behavioural and brain sciences unit,institute of child health,university college london,london, United Kingdom, department of medical genetics,university medical center utrecht,utrecht, Netherlands, wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, department of medical genetics,university of helsinki,helsinki, Finland, department of medical genetics,university of helsinki,helsinki, Finland, department of medical genetics,university of helsinki,helsinki, Finland, academic department of child and adolescent psychiatry,institute of psychiatry,king's college london,london, United Kingdom, social genetic developmental psychiatry centre,institute of psychiatry,king's college london,london, United Kingdom, academic department of child and adolescent psychiatry,institute of psychiatry,king's college london,london,united kingdom,social genetic developmental psychiatry centre,institute of psychiatry,king's college london,london, United Kingdom, division of molecular genome analysis,german cancer research center (dkfz),heidelberg, Germany, division of molecular genome analysis,german cancer research center (dkfz),heidelberg, Germany, department of child and adolescent psychiatry,psychosomatics and psychotherapy,goethe university,frankfurt am main, Germany, department of child and adolescent psychiatry,psychosomatics and psychotherapy,goethe university,frankfurt am main, Germany, department of child and adolescent psychiatry,psychosomatics and psychotherapy,goethe university,frankfurt am main, Germany, department of child and adolescent psychiatry,psychosomatics and psychotherapy,goethe university,frankfurt am main, Germany, department of child and adolescent psychiatry,psychosomatics and psychotherapy,goethe university,frankfurt am main, Germany, department of biology,university of bologna,bologna, Italy, department of biology,university of bologna,bologna, Italy, division of child neurology and psychiatry,department of paediatrics,university of catania,catania, Italy, stella maris clinical research institute for child and adolescent neuropsychiatry,pisa, Italy, division of child neurology and psychiatry,department of pediatrics,university of catania,catania, Italy, department of biology,university of bologna,bologna, Italy, instituto nacional de saude dr ricardo jorge,lisbon,portugal,instituto gulbenkian de ciencia,oeiras,portugal,center for biodiversity,functional and integrative genomics,faculdade de ciências da universidade de lisboa,lisboa, Portugal, instituto nacional de saude dr ricardo jorge,lisbon,portugal,instituto gulbenkian de ciencia,oeiras,portugal,center for biodiversity,functional and integrative genomics,faculdade de ciências da universidade de lisboa,lisboa, Portugal, instituto nacional de saude dr ricardo jorge,lisbon,portugal,instituto gulbenkian de ciencia,oeiras,portugal,center for biodiversity,functional and integrative genomics,faculdade de ciências da universidade de lisboa,lisboa, Portugal, unidade neurodesenvolvimento e autismo,centro investigação e formação clinica,hospital pediátrico coimbra e faculdade medicina,universidade coimbra,coimbra, Portugal, the centre for applied genomics,program in genetics and genomic biology,the hospital for sick children,toronto, Canada, the centre for applied genomics,program in genetics and genomic biology,the hospital for sick children,toronto, Canada, centre national de génotypage,evry, France, centre national de génotypage,evry, France, centre national de génotypage,evry, France, inserm u771 and cnrs 6214,angers,france,département de biochimie et génétique,centre hospitalier universitaire,angers, France, cadipa-centre de ressources autisme rhône-alpes,saint egrève, France, genetics department,hôpital couple-enfant,grenoble, France, cadipa-centre de ressources autisme rhône-alpes,saint egrève, France, assistance publique-hôpitaux de paris,robert debré hospital,department of child and adolescent psychiatry,paris, France, inserm,u955,psychiatrie génétique,créteil,france,université paris est,faculté de médecine,créteil,france,ap-hp,hôpital h. mondor-a. chenevier,département de psychiatrie,créteil, France, gillberg neuropsychiatry centre,university of gothenburg,göteborg,sweden,institute of child health,university college london,london, United Kingdom, institute of anatomy and cell biology,ulm university,ulm, Germany, human genetics and cognitive functions,institut pasteur,paris,france,cnrs ura 2182 genes,synapses and cognition,institut pasteur,paris,france,university denis diderot paris 7,paris, France
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Authors
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|